Laminate assemblies, such as sealed pockets, blisters and packs (in the form of strips, disks or individual containers) for doses of pharmaceuticals in the form of powders, tablets or capsules are well known in the art. As applied in dry powder inhaler (“DPI”) technology, the laminate assemblies (e.g., blister strips) generally comprise a base having cavities, pockets or open “blisters” adapted to receive a pharmaceutical composition (e.g., inhalable dry powder). A lid encloses the opening of each cavity or blister, and an adhesive or bonding layer is disposed between the base and lid to effect a seal for the blister.
The blister base and the blister lid may comprise one or more layers or materials. In their most common forms, blisters typically employ lids comprising aluminum, paper, polyester and combinations, blends or laminates thereof. The materials typically employed for the base include aluminum and various polymeric materials including, but not limited to, polyvinyl chloride (“PVC”), oriented polyamide, and blends or laminates of polymers.
The lid is sealed to the base of the blister in a primary sealing operation. Various known methods are often employed to join the lid and base and, hence, seal the blisters. Such methods include adhesive bonding, hot metal bonding, hot metal welding, radio frequency welding and hot bar sealing.
The primary seal of the base and lid may either by complete wherein the lid and base form are substantially continuously fused along their entire interface in the laminate assembly. In other alternative forms, such as where it is desirable to peel the lid off the base to expose the content of the blister, the seal between the lid and base may comprise a cross-hatched grid of bonds surrounding alternating non-bonded areas. In this way, bonded regions form a generally continuous primary seal may is formed which blocks to a high degree ingress or egress of material, moisture, or impurities between the blister and the external environment.
Several problems are, however, associated with the noted primary sealing. First, the use of adhesive bonding requires tight control of the adhesive parameters and/or characteristics (e.g., flow properties) and the spread of the adhesive to ensure even adhesion of the lid to the base.
The noted welding methods have the disadvantage that tightly controlled physical contact is required between the welding head and the substrate (or strip) to be welded. The welding methods are thus often complex and place a limitation on the speed of the welding process.
Generally, blister strips have seal integrity of a high degree, showing no ingress by methods such as liquid immersion studies. In a liquid immersion study, the blister is immersed in a aqueous dye under a vacuum (25-28 inches mercury/850-950 mbar) for 30 seconds. The pressure is released, and the blister remains submerged for 60 additional seconds. The blister is removed, rinsed, dried and the lid or blister cover is removed to expose the blister contents. Macro-leakage is exemplified if dye is present in the blister contents. It has been found that micro leaks may be present in the bonded area that allow ingress or moisture, yet remain undetected by liquid immersion. It is possible that such micro-leaks may allow moisture in the air to enter into the content of the blister from the external atmosphere, modifying its physical or chemical makeup. A suitable method of addressing micro-leakage is therefore desirable.
Several references in the art generally disclose the use of welding to bond plastic materials. They are not however employed for sealing blisters containing pharmaceutical compositions, particularly, dry powder pharmaceutical compositions for inhalation purposes. Illustrative patents include U.S. Pat. Nos. 4,734,142, 4,767,492, 4,866,914, and GB Pub. Nos. 952,581 and 2,248,796. GB Pub. No. 2,248,796, discloses ultrasonic welding is employed to seal “pouch containers”. No mention is, however, made of laminate assemblies, blister packs or strips for use in the containment of a medicament or pharmaceutical composition.
Dry powder compositions for respirable drugs pose certain challenges to packaging. Dry powders must be manufactured to very tightly controlled within a narrow aerodynamic size range. Only particles having a specific narrow range of aerodynamic size will deposit in the desired location in the pulmonary system. For instance, a particle for local treatment of respiratory conditions, such as asthma, must have a particle size of less than 10 microns, more preferably from 2 to 5 microns. Alternatively for alveolar deposition, particles must be between 1-3 microns in aerodynamic size. A change in the environment in which the composition of particles are contained in packaging may, in some cases, lead to a modification in the aerodynamic behavior of particles. For example, moisture in some materials may play increase particle to particle agglomeration, which causes particles to form larger aggregates, shifting the particle size of aerosolized powder particles outside of this desired range. Larger particles, the result of either moisture swelling or increased agglomeration of smaller particles, will cause the particle(s) to deposit away from the target region of the lung, for example in the device itself, or in the mouth or the throat of the patient. As such agglomeration has been associated with moisture ingress into blister and other packaging, the reduction of the causes of moisture effects has been a desired outcome of the investigations of pharmaceutical manufacturers.
It should be noted that particle sizes, either in aerodynamic or geometric measures, referred to herein relate to a particles effective particle size. Effective particle size denotes the apparent particle size of a body without distinction as to the number of individual particles which go to make up that body, i.e., no distinction is made between the single particle of given size and an agglomerate of the same size which is composed of finer individual particles.
In this endeavor to reduce the impact of moisture or environmental conditions in blisters, the primary seal integrity of laminate structures has been investigated. Suprisingly, it has been found that seals formed as a result of primary sealing are not always formed such that all avenues of ingress into the interior of the blister are eliminated. When such pathways between the blister interior and external environment remain after primary sealing, moisture can enter the blister and cause chemical or physical change, thus negatively impacting the characteristics of the blister contents. Such “leaks” in the primary seal may result from the lid and base mating surfaces not being brought into intimate contact with each other to undergo sufficient bonding. The applicant's investigations have determined is may occur, in some instances, when excess powder is deposited on the base material about the periphery of the blister, rather than solely in the blister. When the lid is placed over the base, this deposited excess powder separates the bonding layers of the two. When sealing conditions (such as heat, energy and/or pressure) is applied, a cavity remains between the base and the lid surrounding this excess material. Other sources of leaks may also exist, such as a failure of machinery dies to closely associate base and lid layers.
In some instances, the seal may not form and a leak will exist after primary sealing. In other instances though, the area around the periphery of the blister is not itself sealed, but is a adjacent to a sealed area. If the sealed area is cut away during subsequent processing, or the sealed portion is otherwise breached, the non-sealed pocket becomes a pathway for moisture ingress. An example of subsequent processing may occur, for example, by trimming the edges of a formed blister in order to make the strip with an appropriate width to be placed in a given device. Such devices include the dry powder inhaler Diskus® device marketed by GlaxoSmithKline, which is depicted in U.S. Pat. No. 5,873,360, (which is incorporated herein by reference).
Subsequent processing, such as trimming, may also disrupt the fused bond between base and lid, causing additional leakage. Hence, processing in some instances may increase the number or the severity of leaks on the blister strip. These causes of leakage are relatively rare, however, in pursing the best products available for delivering medication, reduction of such leaks is desirable.
It is therefore an object of the present invention to provide a method and system for forming a laminate assembly that fuses leaks in a primary seal by including a secondary seal positioned over a portion of the primary seal of the laminate assembly. The secondary seal may be formed by any suitable mechanism, for example a heated pneumatic press (a.k.a. a hot bar/ridge press) or an ultrasonic welding device. The secondary seal heals leaking blister sections, while not adversely impacting the integrity of non-leaking regions of the primary seal.
It is another object of the invention to provide a method and system for forming a laminate assembly that substantially simultaneously fuses and shears the laminate assembly between the blister pocket and the edges of the laminate material.
It is another object of the invention to provide a method and system for forming a laminate assembly that includes the step of providing a secondary seal via hot bar heat sealing, or ultrasonic means.
It is another object of the invention to provide a method and system for forming a laminate assembly having primary and secondary seal regions.
It is another object of the invention to provide a method and system for forming a laminate assembly containing a pharmaceutical composition that employs heat seal to form a primary seal, mechanical shearing of a portion of the sealed material, followed by a secondary sealing step, for example by hot bar sealing or ultrasonic sealing, to form a laminate assembly having a reduced degree of moisture ingress as compared to solely primarily sealed laminate assemblies.
It is another object of the invention to provide a method and system for forming a laminate assembly that includes pre-filling each blister in the base layer with a pharmaceutical composition, sealing the laminate assembly, shearing the laminate assembly to a specific size and/or shape, and then providing a secondary seal to the laminate assembly to cure leaks in the laminate existing after shearing. Secondary sealing may occur before, simultaneously with or after shearing.
It is a yet further objective of the present invention to provide a laminate assembly with a primary seal and a substantially continuous secondary seal along the edge(s) of the laminate assembly.
It is yet another object of the invention to provide packaging for a dry powder pharmaceutical composition having primary and secondary seals that enhance the stability of the pharmaceutical composition.
It is a still further or alternative object of the present invention to a provide a secondary seal which bonds regions of a base and lid material to form a coupled layer enveloping a fused polymeric layer therebetween.